Conformational Flexibility of Pyruvate Dehydrogenase Complexes: A Computational Analysis by Quantized Elastic Deformational Model

Kong, Ying; Ming, Dengming; Wu, Yinghao; Stoops, James K; Zhou, Zheng; Ma, Jianpeng

doi:10.1016/s0022-2836(03)00555-2

Cited by 35 publications

(30 citation statements)

References 30 publications

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“…When analyzing dynamics, we should eliminate external motion by applying the Eckart Condition 29 (9) First derivatives can also be calculated accordingly (10) where (11) P is an operator in matrix form. Then, we have the kinetic matrix (12) We end up with solving a generalized eigenvalue problem (13) After obtaining eigenvectors, we can get orthonormal vectors in CC. (14) Finally, we define a quantitative localization factor T for the "tip effect" (15) The larger the T, the more eminent the "tip effect".…”

Section: Generalized Eigenvalue Problem In Icmentioning

confidence: 99%

“…In recent years, elastic normal-mode analysis (eNMA) has been popularized for its simplicity and wide-range applicability. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] The potential function 1 used in the conventional eNMA 5 is a highly coarse-grained elastic network that has a form of (1) where |r ij | and |r ij 0 | are the instantaneous and equilibrium values (or initial values from the coordinates) of pairwise distance between the ith and the jth Cα atoms, respectively. The value of Heavidide step function σ ij specifies the effect of cutoff.…”

Section: Introductionmentioning

confidence: 99%

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A New Method for Coarse-Grained Elastic Normal-Mode Analysis

Poon

2006

J. Chem. Theory Comput.

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In this paper, we report a new method for coarse-grained elastic normal-mode analysis. The purpose is to overcome a long-standing problem in the conventional analysis called the tip effect that makes the motional patterns (eigenvectors) of some low-frequency modes irrational. The new method retains the merits of a conventional method such as not requiring lengthy initial energy minimization, which always distorts structures, and also delivers substantially more accurate lowfrequency modes with no tip effect for proteins of any size. This improvement of modes is crucial for certain types of applications such as structural refinement or normal-mode-based sampling.

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Section: Generalized Eigenvalue Problem In Icmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A New Method for Coarse-Grained Elastic Normal-Mode Analysis

Poon

2006

J. Chem. Theory Comput.

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“…The resulting model has 12 trimers containing one E3BP that associates to form 6 E3BP dimer connections and 8 trimers containing only E2 that only associate via E2-E2 connections along the 2-fold axis with the 24 E2 subunits in the 12 E3BP-containing trimers. The above ball and socket connections along the 2-fold axis between E2 subunits expand and contract to cause substantial variation (up to 36 Å) in the diameter of the inner core of an E2 oligomer (31,58). 3 This symmetric arrangement of the 6 substituted dimers and the full flexibility of the 8 trimers would maximize the capacity of the inner core to "breathe" in a coordinated fashion.…”

Section: Figmentioning

confidence: 99%

Organization of the Cores of the Mammalian Pyruvate Dehydrogenase Complex Formed by E2 and E2 Plus the E3-binding Protein and Their Capacities to Bind the E1 and E3 Components

Hiromasa

Fujisawa

Aso

et al. 2004

Journal of Biological Chemistry

112

143

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The subunits of the dihydrolipoyl acetyltransferase (E2) component of mammalian pyruvate dehydrogenase complex can form a 60-mer via association of the Cterminal I domain of E2 at the vertices of a dodecahedron. Exterior to this inner core structure, E2 has a pyruvate dehydrogenase component (E1)-binding domain followed by two lipoyl domains, all connected by mobile linker regions. The assembled core structure of mammalian pyruvate dehydrogenase complex also includes the dihydrolipoyl dehydrogenase (E3)-binding protein (E3BP) that binds the I domain of E2 by its C-terminal I domain. E3BP similarly has linker regions connecting an E3-binding domain and a lipoyl domain. The composition of E2⅐E3BP was thought to be 60 E2 plus ϳ12 E3BP. We have prepared homogenous human components. E2 and E2⅐E3BP have s 20,w values of 36 S and 31.8 S, respectively. Equilibrium sedimentation and small angle x-ray scattering studies indicate that E2⅐E3BP has lower total mass than E2, and small angle x-ray scattering showed that E3 binds to E2⅐E3BP outside the central dodecahedron. In the presence of saturating levels of E1, E2 bound ϳ60 E1 and maximally sedimented 64.4 ؎ 1.5 S faster than E2, whereas E1-saturated E2⅐E3BP maximally sedimented 49.5 ؎ 1.4 S faster than E2⅐E3BP. Based on the impact on sedimentation rates by bound E1, we estimate fewer E1 (ϳ12) were bound by E2⅐E3BP than by E2. The findings of a smaller E2⅐E3BP mass and a lower capacity to bind E1 support the smaller E3BP substituting for E2 subunits rather than adding to the 60-mer. We describe a substitution model in which 12 I domains of E3BP replace 12 I domains of E2 by forming 6 dimer edges that are symmetrically located in the dodecahedron structure. Twelve E3 dimers were bound per E2 48 ⅐E3BP 12 mass, which is consistent with this model.The mitochondrial pyruvate dehydrogenase complex (PDC) 1 catalyzes the irreversible conversion of pyruvate to acetyl-CoA along with the reduction of NAD ϩ . PDCs from all known sources contain the pyruvate dehydrogenase (E1), the dihydrolipoyl acetyltransferase (E2), and the dihydrolipoyl dehydrogenase (E3) components. Mammalian PDC has a highly organized structure in which the E2 component plays a central role in the organization, integrated chemical reactions, and regulation of the complex (1-5). Besides those universal components, the mammalian and subsequently some other eukaryotic PDCs were shown to contain another component, called E3-binding protein (E3BP); this protein was originally designated protein X (6, 7). Mammalian E3BP was first characterized as a component with a reactive lipoyl group on a single lipoyl domain (7-11) that, alone, could support the overall reaction (12). E3BP was tightly bound to E2 (7) by its C-terminal region (10). The E3BP component was then shown to contribute to the organization of the complex by binding the E3 component (13)(14)(15)(16)(17)(18). This work provides new insights into the integration of E3BP into the central framework of the mammalian complex.Although first characterized in the bo...

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“…For many large systems, the method offers a way to reliably compute the global conformational motions at almost any experimentally accessible resolutions. Since the introduction of the method [26,27], there have been many applications of QEDM on very large molecular complexes [31][32][33][34]. Many more applications are expected to come in the near future.…”

Section: Normal Mode Analysis Based On Low-resolution Density Mapsmentioning

confidence: 99%

New Advances in Normal Mode Analysis of Supermolecular Complexes and Applications to Structural Refinement

Ma¹

2004

curr protein pept sci

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Normal mode analysis is an effective computational method for studying large-amplitude lowfrequency molecular deformations that are ubiquitously involved in the functions of biological macromoleccules, especially supermolecular complexes. The recent years have witnessed a substantial advance in methodology development in the field. This review is intended to summarize some of the important advances that enable one to simulate deformations of supermolecular complexes at expended resolution-and length-scales, with particular emphasis on the implications in structural refinement against low-to intermediate-resolution structural data such as those from electron cryomicroscopy and fibre diffraction.

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Conformational Flexibility of Pyruvate Dehydrogenase Complexes: A Computational Analysis by Quantized Elastic Deformational Model

Cited by 35 publications

References 30 publications

A New Method for Coarse-Grained Elastic Normal-Mode Analysis

A New Method for Coarse-Grained Elastic Normal-Mode Analysis

Organization of the Cores of the Mammalian Pyruvate Dehydrogenase Complex Formed by E2 and E2 Plus the E3-binding Protein and Their Capacities to Bind the E1 and E3 Components

New Advances in Normal Mode Analysis of Supermolecular Complexes and Applications to Structural Refinement

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